4. Identify new longevity genes and describe their modulation by nutritional and
environmental factors in animals and humans.

1b.Approach (from AD-416)
Because the predisposition to most common ailments affecting healthy aging and the responses of the individual to nutrients both contain a strong genetic component, our approach aims to uncover sets of genes involved in the predisposition to alterations in fasting and non fasting lipid metabolism and obesity and dietary response and to describe specific gene-diet interactions. This will be tested, using high throughput genotyping techniques, both in ongoing studies of free-living populations from different ethnic groups and in the metabolic ward (intervention studies). Our primary focus is to describe gene-diet interactions affecting/influencing progression of the metabolic syndrome, in particular obesity and dyslipidemia, often precursors to cardiovascular disease and diabetes. Cardiovascular candidate genes, both those previously described in the literature as well as those we identify through new genetic technologies and bioinformatics analysis will be used to examine associations and interactions on various scales. These include genetic variations, disease-related phenotypes and specific nutrients [fatty acids, cholesterol, fiber) and behavioral habits (alcohol consumption, smoking, physical (in-activity]. Rigorous statistical analysis will uncover the associations between phenotypes indicative of increased risk of metabolic syndrome and the genes responsible for such. Because cardiovascular disease and diabetes are traditionally considered diseases of the aged, we will also continue with our investigations to identify genes responsible for healthy aging. The principal approach taken for these studies involves gene expression microarray in silico analysis of animal models of aging and longevity. Candidate aging genes will then be studied in human populations.

3.Progress Report
This project includes the work of one subordinate project at the HNRCA funded through a Specific Cooperative Agreement with Tufts University. For further information and progress reports, see 1950-51520-012-01S Nutrition, Cardovascular Health and Genomics.

4.Accomplishments
1.
Discovery of new genes associated with blood lipids in humans. Blood lipid concentrations are heritable risk factors for cardiovascular disease(CVD), but most of their heritability remains unexplained. This hampers the ability to predict an individual’s risk for CVD and consequently to successfully prevent this disease. To fill this gap, ARS-funded researchers from Tufts University in Boston, in collaboration with an international consortium, have thoroughly analyzed the genomes of over 100,000 individuals of European ancestry. This is the largest and more comprehensive study ever conducted to elucidate the genetic basis of cardiovascular risk factors. We identified 95 distinct genes reproducibly associated with lipoprotein concentrations, including 59 genes that were found to be significant for the first time. Moreover, we have shown that some of these genes have a significant impact in blood lipid levels in non-European populations (East Asians, South Asians and African Americans). These discoveries provide the foundation to develop a broader and deeper understanding of lipoprotein metabolism and to identify new preventive and therapeutic opportunities for the prevention of CVD.

2.
New method for the statistical analysis of massive amounts of genetic data. Genetic studies represent the new frontier in Biology and Medicine and their application to large populations allow the generation of vast amounts of data and their analysis and interpretation will allow new discoveries in basic and applied research. However, current statistical approaches are extremely resource intensive requiring powerful mainframe computers and long periods of processing time. This major limitation is impairing the progress of this most important area of translational research. Therefore, ARS-funded researchers from Tufts University in Boston, in collaboration with ARS scientists have developed a combination of new statistical technique that overcomes current technical challenges. This new technology has been successfully tested and implemented using genomic information from datasets in humans, dog and maize. This approach dramatically reduced computing time from years to days without compromising the quality of the results. This development will increase vastly the capacity to carry out and analyze larger datasets in order to accelerate the path of discovery in biomedical research.

3.
A common genetic variant in the APOA2 gene determines dietary intake and obesity. The prevalence of obesity and overweight continues to increase to a level without precedent in U.S. history and is an important underlying cause of many related disorders, as well as escalating health care costs. Therefore, there is critical need for effective, proven methods for the primary prevention of weight gain. However, we don’t have the tools to predict the individual risk as well as responses to therapeutic recommendations. Therefore, ARS-funded researchers from Tufts University in Boston conducted a large study to investigate the role of a functional genetic variant, known as APOA2 -265T>C, in the regulation of food intake and body weight. Three independent populations in the United States were examined: the Framingham Offspring Study (1454 whites), the Genetics of Lipid Lowering Drugs and Diet Network Study (1078 whites), and Boston-Puerto Rican Centers on Population Health and Health Disparities Study (930 Hispanics of Caribbean origin). The results of this study show that people carrying the genetic variant at the APOA2 gene developed obesity only in the presence of a high saturated fat diet. This was true for the three populations and this is the first time that such replication is achieved across populations in research involving gene and diet interactions. This finding will contribute to the identification of individuals susceptible to diet-induced obesity. Moreover, it will guide the implementation of tailored dietary recommendations to specifically quench their increased predisposition to obesity and cardiovascular diseases.